US4504490A - Substituted benzenesulfonic esters and their use as medicaments for combatting helminths - Google Patents
Substituted benzenesulfonic esters and their use as medicaments for combatting helminths Download PDFInfo
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- US4504490A US4504490A US06/528,842 US52884283A US4504490A US 4504490 A US4504490 A US 4504490A US 52884283 A US52884283 A US 52884283A US 4504490 A US4504490 A US 4504490A
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- 150000002148 esters Chemical class 0.000 title claims abstract description 10
- 244000000013 helminth Species 0.000 title claims abstract description 5
- 239000003814 drug Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 17
- -1 1,1,2,2-tetrafluoroethoxy Chemical group 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- JYUMDXXUCXSCFM-UHFFFAOYSA-N [3-[[(z)-n,n'-bis(methoxycarbonyl)carbamimidoyl]amino]-4-(carbamoylamino)phenyl] 3-(trifluoromethyl)benzenesulfonate Chemical compound C1=C(NC(N)=O)C(NC(NC(=O)OC)=NC(=O)OC)=CC(OS(=O)(=O)C=2C=C(C=CC=2)C(F)(F)F)=C1 JYUMDXXUCXSCFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 241001465754 Metazoa Species 0.000 abstract description 3
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 125000001309 chloro group Chemical group Cl* 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 7
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000007868 Raney catalyst Substances 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
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- 230000000507 anthelmentic effect Effects 0.000 description 5
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- 230000003197 catalytic effect Effects 0.000 description 5
- 150000002828 nitro derivatives Chemical class 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical class OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CBQNJOWKUBLTSF-UHFFFAOYSA-N [3-amino-4-(carbamoylamino)phenyl] 3-(trifluoromethyl)benzenesulfonate Chemical compound C1=C(N)C(NC(=O)N)=CC=C1OS(=O)(=O)C1=CC=CC(C(F)(F)F)=C1 CBQNJOWKUBLTSF-UHFFFAOYSA-N 0.000 description 3
- HLKRDPGZVNQQAG-UHFFFAOYSA-N [4-(carbamoylamino)-3-nitrophenyl] 3-(trifluoromethyl)benzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)N)=CC=C1OS(=O)(=O)C1=CC=CC(C(F)(F)F)=C1 HLKRDPGZVNQQAG-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- MFTAJEZTEQICND-UHFFFAOYSA-N carbamothioylcarbamic acid Chemical compound NC(=S)NC(O)=O MFTAJEZTEQICND-UHFFFAOYSA-N 0.000 description 3
- UPJWAKUNQVOESN-UHFFFAOYSA-N carbonisothiocyanatidic acid Chemical compound OC(=O)N=C=S UPJWAKUNQVOESN-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- LBFAAYMITJMZOC-UHFFFAOYSA-N methyl n-(sulfanylidenemethylidene)carbamate Chemical compound COC(=O)N=C=S LBFAAYMITJMZOC-UHFFFAOYSA-N 0.000 description 3
- KHBXLYPOXVQKJG-UHFFFAOYSA-N methyl n-[(methoxycarbonylamino)-methylsulfanylmethylidene]carbamate Chemical compound COC(=O)NC(SC)=NC(=O)OC KHBXLYPOXVQKJG-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- YSAPYRFQLHBJSV-UHFFFAOYSA-N phenyl 3-amino-4-(carbamoylamino)benzenesulfonate Chemical compound C1=C(N)C(NC(=O)N)=CC=C1S(=O)(=O)OC1=CC=CC=C1 YSAPYRFQLHBJSV-UHFFFAOYSA-N 0.000 description 3
- SDILANDQXWIRDR-UHFFFAOYSA-N phenyl 4-(carbamoylamino)-3-nitrobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(NC(=O)N)=CC=C1S(=O)(=O)OC1=CC=CC=C1 SDILANDQXWIRDR-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
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- 239000007900 aqueous suspension Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical class ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 208000006275 fascioliasis Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- GTQKFVRTZFWEBC-UHFFFAOYSA-N phenyl 3-[[(z)-n,n'-bis(methoxycarbonyl)carbamimidoyl]amino]-4-(carbamoylamino)benzenesulfonate Chemical compound C1=C(NC(N)=O)C(NC(NC(=O)OC)=NC(=O)OC)=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 GTQKFVRTZFWEBC-UHFFFAOYSA-N 0.000 description 1
- BNXKFGPXKCNHMD-UHFFFAOYSA-N phenyl 4-(acetylcarbamoylamino)-3-(methoxycarbonylcarbamothioylamino)benzenesulfonate Chemical compound C1=C(NC(=O)NC(C)=O)C(NC(=S)NC(=O)OC)=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 BNXKFGPXKCNHMD-UHFFFAOYSA-N 0.000 description 1
- CSWATSLUQPFDDW-UHFFFAOYSA-N phenyl 4-(carbamoylamino)-3-(methoxycarbonylcarbamothioylamino)benzenesulfonate Chemical compound C1=C(NC(N)=O)C(NC(=S)NC(=O)OC)=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 CSWATSLUQPFDDW-UHFFFAOYSA-N 0.000 description 1
- JXBMHGKZPCOWBL-UHFFFAOYSA-N phenyl 4-(chlorosulfonylcarbamoylamino)-3-nitrobenzenesulfonate Chemical compound C1=C(NC(=O)NS(Cl)(=O)=O)C([N+](=O)[O-])=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 JXBMHGKZPCOWBL-UHFFFAOYSA-N 0.000 description 1
- NEZIKMJTIOLUGU-UHFFFAOYSA-N phenyl 4-amino-3-nitrobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1S(=O)(=O)OC1=CC=CC=C1 NEZIKMJTIOLUGU-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/75—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/66—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfo, esterified sulfo or halosulfonyl groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/28—Y being a hetero atom, e.g. thiobiuret
Definitions
- the present invention relates to new substituted Benzenesulfonic esters, a process for their preparation and the use as medicaments, in particular as anthelminthics.
- R 1 denotes straight-chain or branched alkyl having 1-4 carbon atoms
- n denotes 1, 2 or 3
- the individual substituents R 2 independently of one another, denote hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, 1,1,2,2-tetrafluoroethoxy, straight-chain or branched alkyl having 1-12 carbon atoms, cycloalkyl having 3-8 carbon atoms, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each having 1-6 carbon atoms in the alkyl radical, acetyl, acetamino, or phenyl, phenoxy, phenylthio, phenylsulfinyl or phenyls
- X denotes --SO 2 --O-- or --O--SO 2 --
- Z denotes ⁇ S; ⁇ N--COOR 1 or ⁇ NH.
- R 1 denotes methyl and R 2 denotes hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, 1,1,2,2-tetrafluoroethoxy, straight-chain or branched alkyl having 1-6 carbon atoms or cycloalkyl having 3-6 carbon atoms, and
- R 3 denotes hydrogen or --COR 4 , in which R 4 denotes alkyl or alkoxyalkyl, each having 1-4 carbon atoms in an alkyl moiety, or phenyl,
- X denotes --SO 2 --O-- or --O--SO 2 --
- Z denotes ⁇ S or ⁇ NCOOCH 3 and n denotes 1 or 2.
- the invention also relates to a process for the preparation of substituted benzenesulfonic esters of the formula I, which comprises reacting an aminourea derivative of the formula II ##STR3## in which R 2 , R 3 , X and n have the same meaning as in formula I, either
- R 1 has the abovementioned meaning, to give a compound of the formula I, in which
- Z represents S, or
- Z denotes ⁇ N--COOR 1 ,
- Z denotes ⁇ N--COOR 1 ,
- Z represents ⁇ NH.
- Nitroamines of the formula VII are known from German Offenlegungsschrift No. 2,441,201 and German Offenlegungsschrift No. 2,441,202 (corresponding to U.S. Pat. No. 3,996,368 and U.S. Pat. No. 3,996,369) and are prepared by the methods given there or by analogous routes.
- X in formula VII denotes --SO 2 --O--
- the preparation is advantageously carried out by reaction of an optionally R 2 n -substituted benzenesulfonyl chloride with 4-amino-3-nitrophenol or its salt in an inert solvent such as acetone, in the presence of an organic or inorganic base, such as triethylamine or sodium hydroxide.
- X in formula VII denotes --O--SO 2 --
- the preparation is advantageously carried out by reaction of an optionally R 2 n -substituted phenol with 4-chloro-3-nitrobenzenesulfonyl chloride in an inert solvent such as acetone, in the presence of an organic or inorganic base, such as triethylamine or sodium hydroxide and subsequent chlorine exchange in an inert solvent, such as dioxane, with gaseous ammonia at elevated temperature, advantageously at 100°-140° C. and under elevated pressure.
- an organic or inorganic base such as triethylamine or sodium hydroxide
- the reaction of the nitroamines of the formula VII with N-chlorosulfonyl isocyanate VIII takes place in an aprotic solvent at -20° to +50° C., preferably between 0° and 20° C.
- suitable solvents are hydrocarbons, such as hexane, cyclohexane, benzene, toluene or xylene, ethers, such as diisopropyl ether, dioxane or dimethoxyethane, or chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or chlorobenzene, and acetonitrile.
- a slight excess (10-20%) of VIII in toluene is employed at about 10° C.
- the hydrolysis of the sulfochlorides VI takes place by stirring with water or an aqueous solution of an inorganic or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, optionally with the addition of a solvent, such as methanol, ethanol or acetone, at -20° to +100° C.
- the reaction is preferably carried out at 0° to 80° C. in 1-2N HCl.
- an excess of the acid anhydride is used at 0°-40° C. and concentrated sulfuric acid is used as the catalyst.
- nitro compounds of the formula V are hydrogenated to give the amino compounds of the formula II by reduction, for example with Raney nickel, in a solvent, for example methanol or dimethylformamide, under normal pressure or in an autoclave under pressure.
- the reaction of the amino compounds II with an isothiocyanatocarboxylate III is carried out with or without the addition of a solvent at -20° to +140° C.
- suitable solvents are: diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, acetone, butanone, toluene, xylene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, methanol, ethanol, isopropanol or 2-methoxyethanol.
- the reaction is preferably carried out with an equimolar amount or a slight excess (10-20%) of the isothiocyanatocarboxylate at 20°-50° C. in dioxane or ethyl acetate.
- Suitable solvents are, in particular, polar solvents, such as, for example, water, methanol, ethanol, isopropanol, butanol or 2-methoxyethanol, but also, for example, ethyl acetate, dioxane, toluene, chloroform or mixtures thereof.
- Acids which can be used are inorganic or organic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid and p-toluenesulfonic acid.
- the reaction is preferably carried out in methanol, alone or mixed with ethyl acetate, with the addition of glacial acetic acid or p-toluenesulfonic acid at the reflux temperature of the mixture used.
- Z denotes ⁇ NH.
- Suitable bases are ammonia, alkali metal or alkaline earth metal carbonates and hydroxides, such as potassium or barium carbonate, sodium or potassium hydroxide or amines, such as methylamine, ethylamine, butylamine, diethylamine, diisopropylamine, triethylamine or ethyl diisopropylamine, in a solvent, such as water, methanol, ethanol, isopropanol, ethyl acetate, acetone, dioxane, toluene or mixtures of these.
- the temperature used for this reaction can be between 0° and 120° C.
- butylamine is used in methanol, advantageously at the boiling point of the reaction mixture.
- Z denotes ⁇ NCOOR 1 or ⁇ NH
- the new substituted benzenesulfonic esters of the formula I according to the invention are valuable chemotherapeutic agents and are suitable for controlling parasitic diseases of humans and animals.
- helminths for example Haemonchus, Trichostrongylus, Ostertagia, Cooperia, Chabertia, Strongyloides, Oesophagostomum, Hyostrongylus, Ancylostoma, Ascaris and Heterakis as well as Fasciola.
- helminths for example Haemonchus, Trichostrongylus, Ostertagia, Cooperia, Chabertia, Strongyloides, Oesophagostomum, Hyostrongylus, Ancylostoma, Ascaris and Heterakis as well as Fasciola.
- the efficacy against gastrointestinal strongylidae, lung worms and liver flukes by which, in particular, domestic and useful animals are affected.
- the compounds according to the invention will be particularly used in verterinary medicaments.
- the compounds of the formula I will be administered, depending on the status of the case, in doses between 0.1 and 50 mg per kg of body weight for 1 to 14 days.
- Suitable for oral administration are tablets, coated tablets, capsules, boli, powders, granules or pastes, which contain the active compounds together with customary auxiliaries or vehicles, such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silica, carboxymethylcellulose or similar materials.
- customary auxiliaries or vehicles such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silica, carboxymethylcellulose or similar materials.
- solutions are suitable for parenteral administration, for example oily solutions which are prepared using sesame oil, olive oil or synthetic triglycerides, optionally with an additive, such as, for example, tocopherol as an antioxidant, and/or the use of surface-active materials, such as sorbitan fatty acid esters.
- Aqueous suspensions are also suitable, these being prepared using ethoxylated sorbitan fatty acid esters, and/or with the addition of thickening agents, such as polyethylene glycol or carboxymethylcellulose.
- concentrations of the active compounds according to the invention in the products prepared from them are preferably between 0.5 and 25 percent by weight for use as veterinary medicaments; the concentrations of the active compounds are preferably between 20 and 80 percent by weight for use as human medicaments.
- the new aminourea derivatives of the formula II and the new nitro compounds of the formula V likewise have anthelminthic efficacy.
- they can be used, as can the new sulfochlorides of the formula VI, as intermediates for the preparation of anthelminthics as described above.
- the solid is dissolved in dimethylformamide at about 50° C., treated with active charcoal, filtered, ethyl acetate and diisopropyl ether are added and crystallization is allowed to occur, melting point 193° C., decomposition.
- X denotes --O--SO 2 --
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19823232959 DE3232959A1 (de) | 1982-09-04 | 1982-09-04 | Substituierte benzolsulfonsaeureester, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
DE3232959 | 1982-09-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4504490A true US4504490A (en) | 1985-03-12 |
Family
ID=6172503
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/528,842 Expired - Fee Related US4504490A (en) | 1982-09-04 | 1983-09-02 | Substituted benzenesulfonic esters and their use as medicaments for combatting helminths |
Country Status (20)
Country | Link |
---|---|
US (1) | US4504490A (el) |
EP (1) | EP0105196B1 (el) |
JP (1) | JPS5976050A (el) |
KR (1) | KR840006335A (el) |
AT (1) | ATE28630T1 (el) |
AU (1) | AU1867983A (el) |
CA (1) | CA1214182A (el) |
DE (2) | DE3232959A1 (el) |
DK (1) | DK401683A (el) |
ES (2) | ES8500898A1 (el) |
FI (1) | FI833119A (el) |
GR (1) | GR78941B (el) |
HU (1) | HU193531B (el) |
IL (1) | IL69640A0 (el) |
MA (1) | MA19892A1 (el) |
NO (1) | NO833158L (el) |
NZ (1) | NZ205468A (el) |
PH (1) | PH19980A (el) |
PT (1) | PT77285B (el) |
ZA (1) | ZA836515B (el) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4797427A (en) * | 1987-04-25 | 1989-01-10 | Bayer Aktiengesellschaft | Aromatic diamines containing sulfonic acid aryl esters, a process for their production and their use in the production of polyurethane plastics |
WO1993011761A1 (en) * | 1991-12-18 | 1993-06-24 | H. Lundbeck A/S | Aryl-triflates and related compounds |
WO2012142698A1 (en) * | 2011-04-20 | 2012-10-26 | Universite Laval | Alkylurea derivatives active against cancer cells |
US20230202220A1 (en) * | 2020-05-07 | 2023-06-29 | Koehler Innovation & Technology Gmbh | Heat-sensitive recording material |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0742208A1 (en) * | 1995-05-05 | 1996-11-13 | Grelan Pharmaceutical Co., Ltd. | 2-Ureido-benzamide derivatives |
ES2394211T3 (es) | 2000-06-20 | 2013-01-23 | Novartis Ag | Procedimiento de administración de bifosfonatos |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3996369A (en) * | 1974-08-28 | 1976-12-07 | Hoechst Aktiengesellschaft | Anthelmintically active 2-carbalkoxyamino benzimidazolyl-5(6)-sulfonic acid phenyl esters |
US3996368A (en) * | 1974-08-24 | 1976-12-07 | Hoechst Aktiengesellschaft | Anthelmintically active 2-carbalkoxyamino-5(6)-phenyl sulfonyloxy benzimidazoles |
US4176192A (en) * | 1976-02-28 | 1979-11-27 | Hoechst Aktiengesellschaft | Substituted phenylguanidines and process for their manufacture |
US4194004A (en) * | 1976-11-26 | 1980-03-18 | Bayer Aktiengesellschaft | Substituted benzenesulphonic acid esters, processes for their preparation and their use as medicaments |
US4254143A (en) * | 1978-08-19 | 1981-03-03 | Hoechst Aktiengesellschaft | Monocarboxylates of phenylguanidinesulfonic acid esters, a process for their manufacture, compositions containing them and their use for combating helminths |
-
1982
- 1982-09-04 DE DE19823232959 patent/DE3232959A1/de not_active Withdrawn
-
1983
- 1983-08-31 EP EP83108570A patent/EP0105196B1/de not_active Expired
- 1983-08-31 AT AT83108570T patent/ATE28630T1/de not_active IP Right Cessation
- 1983-08-31 DE DE8383108570T patent/DE3372756D1/de not_active Expired
- 1983-09-01 FI FI833119A patent/FI833119A/fi not_active Application Discontinuation
- 1983-09-02 HU HU833068A patent/HU193531B/hu unknown
- 1983-09-02 ES ES525335A patent/ES8500898A1/es not_active Expired
- 1983-09-02 PT PT77285A patent/PT77285B/pt unknown
- 1983-09-02 GR GR72361A patent/GR78941B/el unknown
- 1983-09-02 NO NO833158A patent/NO833158L/no unknown
- 1983-09-02 DK DK401683A patent/DK401683A/da not_active Application Discontinuation
- 1983-09-02 US US06/528,842 patent/US4504490A/en not_active Expired - Fee Related
- 1983-09-02 JP JP58160602A patent/JPS5976050A/ja active Pending
- 1983-09-02 PH PH29485A patent/PH19980A/en unknown
- 1983-09-02 CA CA000435946A patent/CA1214182A/en not_active Expired
- 1983-09-02 KR KR1019830004133A patent/KR840006335A/ko not_active Application Discontinuation
- 1983-09-02 ZA ZA836515A patent/ZA836515B/xx unknown
- 1983-09-02 NZ NZ205468A patent/NZ205468A/xx unknown
- 1983-09-02 IL IL69640A patent/IL69640A0/xx unknown
- 1983-09-02 AU AU18679/83A patent/AU1867983A/en not_active Abandoned
- 1983-09-03 MA MA20115A patent/MA19892A1/fr unknown
-
1984
- 1984-07-02 ES ES533932A patent/ES533932A0/es active Granted
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3996368A (en) * | 1974-08-24 | 1976-12-07 | Hoechst Aktiengesellschaft | Anthelmintically active 2-carbalkoxyamino-5(6)-phenyl sulfonyloxy benzimidazoles |
US3996369A (en) * | 1974-08-28 | 1976-12-07 | Hoechst Aktiengesellschaft | Anthelmintically active 2-carbalkoxyamino benzimidazolyl-5(6)-sulfonic acid phenyl esters |
US4176192A (en) * | 1976-02-28 | 1979-11-27 | Hoechst Aktiengesellschaft | Substituted phenylguanidines and process for their manufacture |
US4194004A (en) * | 1976-11-26 | 1980-03-18 | Bayer Aktiengesellschaft | Substituted benzenesulphonic acid esters, processes for their preparation and their use as medicaments |
US4254143A (en) * | 1978-08-19 | 1981-03-03 | Hoechst Aktiengesellschaft | Monocarboxylates of phenylguanidinesulfonic acid esters, a process for their manufacture, compositions containing them and their use for combating helminths |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4797427A (en) * | 1987-04-25 | 1989-01-10 | Bayer Aktiengesellschaft | Aromatic diamines containing sulfonic acid aryl esters, a process for their production and their use in the production of polyurethane plastics |
WO1993011761A1 (en) * | 1991-12-18 | 1993-06-24 | H. Lundbeck A/S | Aryl-triflates and related compounds |
WO2012142698A1 (en) * | 2011-04-20 | 2012-10-26 | Universite Laval | Alkylurea derivatives active against cancer cells |
US20230202220A1 (en) * | 2020-05-07 | 2023-06-29 | Koehler Innovation & Technology Gmbh | Heat-sensitive recording material |
Also Published As
Publication number | Publication date |
---|---|
EP0105196A3 (en) | 1985-04-03 |
KR840006335A (ko) | 1984-11-29 |
ES525335A0 (es) | 1984-11-01 |
PT77285B (en) | 1986-04-09 |
ES8500898A1 (es) | 1984-11-01 |
NO833158L (no) | 1984-03-05 |
PT77285A (en) | 1983-10-01 |
ZA836515B (en) | 1984-04-25 |
ES8503649A1 (es) | 1985-03-16 |
ES533932A0 (es) | 1985-03-16 |
MA19892A1 (fr) | 1984-04-01 |
EP0105196B1 (de) | 1987-07-29 |
DE3372756D1 (en) | 1987-09-03 |
PH19980A (en) | 1986-08-26 |
CA1214182A (en) | 1986-11-18 |
DK401683D0 (da) | 1983-09-02 |
HU193531B (en) | 1987-10-28 |
GR78941B (el) | 1984-10-02 |
NZ205468A (en) | 1985-07-31 |
JPS5976050A (ja) | 1984-04-28 |
ATE28630T1 (de) | 1987-08-15 |
EP0105196A2 (de) | 1984-04-11 |
IL69640A0 (en) | 1983-12-30 |
DE3232959A1 (de) | 1984-03-08 |
FI833119A (fi) | 1984-03-05 |
DK401683A (da) | 1984-03-05 |
AU1867983A (en) | 1984-03-08 |
FI833119A0 (fi) | 1983-09-01 |
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